The desmogleins are a family of transmembrane proteins which play an important role in cell adhesion, ensuring that cells within tissue are bound together. In skin, they are major components in desmosomes. Desmosomes are cell-cell adhesion complex between epithelial and certain other cell types. They provide mechanical integrity to keratinocytes by linking to keratin intermediate filaments. Desmogleins form the glue that attaches adjacent skin cells, keeping the skin intact. Desmoglein 1 and 3 are both expressed in stratified squamous epithelia. Desmoglein 1 is dominantly expressed in the differentiated upper layer of epidermis, and Desmoglein 3 is mostly found in basal and suprabasal layers. The differential expression pattern of Desmogleins is important for regulating epidermal functions. Changes of Desmoglein 1 and 3 expression pattern in animal models disrupts keratinocyte proliferation and barrier function of skin. An anticipated benefit for the stimulation of Desmogleins would be an increase in anchoring and adhesion between keratinocytes leading to firmer skin and fewer wrinkles.
Collagen is the body's major structural protein and is composed of three protein chains wound together in a tight triple helix. This unique structure gives collagen a greater tensile strength than steel. Approximately 33 percent of the protein in the body is collagen. This protein supports tissues and organs and connects these structures to bones. In fact, bones are also composed of collagen combined with certain minerals such as calcium and phosphorus. Collagen plays a key role in providing the structural scaffolding surrounding cells that helps to support cell shape and differentiation, similar to how steel rods reinforce a concrete block. The mesh-like collagen network binds cells together and provides the supportive framework or environment in which cells develop and function, and tissues and bones heal.
Collagen is created by fibroblasts, which are specialized skin cells located in the dermis. Fibroblasts also produce other skin structural proteins such as elastin (a protein which gives the skin its ability to snap back) and glucosaminoglycans (GAGs). GAGs make up the ground substance that keeps the dermis hydrated. In order to signal or turn on the production of skin structural proteins, fibroblast cells have specially shaped receptors on their outside membranes that act as binding sites to which signal molecules with a matching shape can fit. When the receptors are bound by the correct combination of signal molecules (called fibroblast growth factors, or FGFs), the fibroblast begins the production of collagen. The stimulation of collagen gives the skin its strength, durability, and smooth, plump appearance.
Dermatopontin is a protein component of the extracellular matrix which is located primarily on the surface of the collagen fibers in the skin. Dermatopontin is believed to play important roles in cell-matrix interactions and matrix assembly (collagen fibrillogenesis). Investigation of dermatopontin knockout mice confirm the involvement of dermatopontin in skin elasticity and collagen accumulation, as the elastic modulus of skin was reported to be 57% lower and collagen content was 40% lower in dermatopontin-null mice than in wild-type mice. Takeda et al., “Targeted disruption of dermatopontin causes abnormal collagen fibrillogenesis,” J. Invest. Dermatol, 2002 September; 119(3):678-83.
It is therefore an object of the invention to provide new compositions and methods for stimulating collagen I, desmogleins, and/or dermatopontin production. It is a further object of the invention to improve the overall appearance of skin, including treating, reversing, and/or preventing signs of aging, such as skin wrinkles, by stimulating collagen I, desmogleins, and/or dermatopontin production with cosmetic compositions comprising effective amounts of 1-aroyl-N-(2-oxo-3-piperidinyl)-2-piperazine carboxamides.
The foregoing discussion is presented solely to provide a better understanding of nature of the problems confronting the art and should not be construed in any way as an admission as to prior art nor should the citation of any reference herein be construed as an admission that such reference constitutes “prior art” to the instant application.